The genetic stability of a conditional live HIV-1 variant can be improved by mutations in the Tet-On regulatory system that restrain evolution.

The Journal of Biological Chemistry
Xue ZhouBen Berkhout

Abstract

Live attenuated human immunodeficiency virus type 1 (HIV-1) vaccines are considered unsafe because more quickly replicating pathogenic virus variants may evolve after vaccination. As an alternative vaccine approach, we have previously presented a doxycycline (dox)-dependent HIV-1 variant that was constructed by incorporating the tetracycline-inducible gene expression system (Tet-On system) into the viral genome. Replication of this HIV-rtTA variant is driven by the dox-inducible transcriptional activator rtTA and can be switched on and off at will. A large scale evolution study was performed to test the genetic stability of this conditional live vaccine candidate. In several long term cultures, we selected for HIV-rtTA variants that no longer required dox for replication. These evolved variants acquired a typical amino acid substitution either at position 19 or 37 in the rtTA protein. Both mutations caused rtTA activity and viral replication in the absence of dox. We designed a novel rtTA variant with a higher genetic barrier toward these undesired evolutionary routes. The corresponding HIV-rtTA variant did not lose dox control in long term cultures, demonstrating its improved genetic stability.

References

Jun 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·M Gossen, H Bujard
Apr 12, 1994·Proceedings of the National Academy of Sciences of the United States of America·J P VartanianS Wain-Hobson
Jul 23, 1996·Proceedings of the National Academy of Sciences of the United States of America·S M SmithK T Jeang
Sep 12, 1998·Nature Medicine·R C Desrosiers
Aug 24, 1999·Biotechnology and Bioengineering·X MazurM Fussenegger
Apr 20, 2000·AIDS Research and Human Retroviruses·T KuwataM Hayami
Jun 22, 2000·Proceedings of the National Academy of Sciences of the United States of America·S UrlingerW Hillen
Aug 15, 2000·Angewandte Chemie·W SaengerW Hinrichs
Oct 29, 2000·AIDS Research and Human Retroviruses·J MillsN Almond
May 17, 2001·Proceedings of the National Academy of Sciences of the United States of America·G MarzioB Berkhout
Jun 9, 2001·The Journal of Biological Chemistry·S M SmithK T Jeang
Aug 7, 2003·Expert Review of Vaccines·Atze T DasBen Berkhout
Feb 6, 2004·The Journal of Biological Chemistry·Atze T DasBen Berkhout
Aug 4, 2004·Methods in Enzymology·Atze T DasBen Berkhout
Nov 11, 2005·Retrovirology·John Brady, Fatah Kashanchi

❮ Previous
Next ❯

Citations

Dec 22, 2011·Nucleic Acids Research·Nicole LundAlan Cochrane
May 19, 2010·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Atze T Das, Ben Berkhout
Jan 24, 2007·BMC Biotechnology·Xue ZhouAtze T Das
Apr 5, 2013·PLoS Pathogens·Raymond W WongAlan Cochrane
Jun 29, 2010·HIV Therapy·Atze T DasBen Berkhout
Jun 1, 2012·The Journal of General Virology·Nicolas LegrandMireille Centlivre
May 20, 2015·Virus Research·Atze T Das, Ben Berkhout
Jan 27, 2017·Retrovirology·Ahalya BalachandranAlan Cochrane
Oct 7, 2017·Journal of Chemical Technology and Biotechnology·Nanxi WangJiantao Guo

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.